Composition containing 7-hydroxy DHEA and/or 7-keto DHEA and at least a carotenoid

ABSTRACT

The invention concerns a composition containing, in a physiologically acceptable medium: (a) at least a DHEA derivative selected among 7-hydroxy DHEA and 7-keto DHEA, and (b) at least a carotenoid. The invention also concerns cosmetic and dermatological uses of said composition, in particular for preventing or treating actinic skin ageing symptoms.

The present invention relates to a composition containing 7-hydroxy-DHEAand/or 7-keto-DHEA and at least one carotenoid, and to the use of saidcomposition, in particular for preventing or treating the signs ofactinic skin aging.

DHEA, or dehydroepiandrosterone, is a natural steroid which is mainlyproduced by the corticoadrenal glands. Exogenous DHEA, administeredtopically or orally, is known for its capacity to promote keratinizationof the epidermis (JP-07 196 467) and to treat dry skins by increasingthe endogenous production and the secretion of sebum and by thusreinforcing the barrier effect of the skin (U.S. Pat. No. 4,496,556).There has also been described in Patent U.S. Pat. No. 5,843,932 the useof DHEA for treating atrophy of the dermis by inhibiting the loss ofcollagen and of connective tissue. Finally, the applicant hasdemonstrated the capacity of DHEA to control the weathered appearance ofthe skin (FR 00/00349), and to modulate the pigmentation of the skin andof the hair (FR 99/12773) and to control atrophy of the epidermis (FR00/06154). These properties of DHEA make it a candidate of choice asanti-aging active agent.

Among the metabolites of DHEA, particular attention has been made in thelast few years to 7α-hydroxy-DHEA. It has indeed been demonstrated thatthis metabolite, which does not possess the hormonal activity of DHEA,made it possible to increase the proliferation of the fibroblasts andthe viability of the human keratinocytes and had anti-free radicaleffects (WO 98/40074). It has also been demonstrated, on rats (WO00/28996), that 7α-hydroxy-DHEA increased the thickness of the dermisand the elastin and collagen content of the skin. It has thus beensuggested to use this metabolite of DHEA for preventing and/or treatingthe harmful effects of UV radiation on the skin, for controllingwrinkles and for increasing skin firmness and tone.

7α-Hydroxy-DHEA is, with 5-androstene-3β,17β-diol, a major metabolite ofDHEA, which is obtained by the action of 7α-hydroxylase on DHEA. Amongthe minor metabolites of DHEA, there may be mentioned 7β-hydroxy-DHEA,which is obtained by the action of 7β-hydroxylase on DHEA and7-keto-DHEA, which is itself a metabolite of 7β-hydroxy-DHEA.

In the remainder of this description, the expression “7-hydroxy-DHEA”will be used to designate without distinction 7α-hydroxy-DHEA and7β-hydroxy-DHEA.

It is now evident to the applicant that the combination of7-hydroxy-DHEA and/or 7-keto-DHEA with a carotenoid could make itpossible to more effectively prevent or treat the signs of skin aging,in particular of actinic aging or photoaging.

The subject of the present invention is therefore a compositioncontaining, in a physiologically acceptable medium: (a) at least oneDHEA derivative chosen from 7-hydroxy-DHEA and 7-keto-DHEA, and (b) atleast one carotenoid.

7-Hydroxy-DHEA is preferably 7α-OH-DHEA. A method for preparing thiscompound is described in particular in Patent Applications FR-2 771 105and WO 94/08588. However, 7β-OH-DHEA is also suitable for use in thepresent invention.

The concentration of DHEA derivative in the composition according to theinvention is advantageously between 0.0000001% and 10% by weight,preferably between 0.00001% and 5% by weight, relative to the totalweight of the composition.

The composition according to the present invention contains, incombination with the DHEA derivative, at least one carotenoid.

The expression carotenoid is understood to mean according to theinvention both a carotenoid with provitamin A activity and a carotenoidwithout provitamin A activity. Among the carotenoids with provitamin Aactivity, there may be mentioned, by way of example, β-carotene orα-carotene. Among the carotenoids without provitamin A activity, theremay be mentioned, by way of example, zeaxanthin, lutein or lycopene.

The carotenoid used according to the invention may be of natural orsynthetic origin. The expression natural origin is understood to meanthe carotenoid, in the pure state or in solution regardless of itsconcentration in said solution, obtained from a natural component. Theexpression synthetic origin is understood to mean the carotenoid, in thepure state or in solution regardless of its concentration in saidsolution, obtained by chemical synthesis.

When the carotenoid is of natural origin, it may be obtained from aplant material derived from a whole plant cultured in vivo or derivedfrom in vitro culture. The expression in vivo culture is understood tomean any culture of the conventional type, that is to say in the soil inthe open air or in a greenhouse, or alternatively with no soil. Theexpression in vitro culture is understood to mean all the techniquesknown to persons skilled in the art which artificially allow theproduction of a plant or of a portion of a plant. The selection pressureimposed by the physicochemical conditions during the growth of plantcells in vitro makes it possible to obtain a standardized plant materialwhich is available throughout the year unlike plants cultured in vivo.

Preferably according to the invention, a plant derived from in vivoculture is used.

Any method of extraction known to persons skilled in the art may be usedto prepare the carotenoid used according to the invention. Thecarotenoid may be in an alcoholic, in particular ethanolic, solution.The carotenoid may also be in a lipid (oil) or lipid-alcohol solution.

The preferred carotenoids according to the invention are β-carotene andlycopene. Most preferably, lycopene is used.

Lycopene is a natural pigment which is found in ripe fruits,particularly in tomato. Its structure is close to that of β-carotene. Itmay be in cis or trans form.

By way of example, according to the invention, there is used alycopene-rich tomato extract prepared by the company Métaphar andmarketed under the name LycOMato® consisting of an oleoresin extract(fatty phase) containing 6% pure lycopene.

It is also possible to use, according to the invention, any preparationcontaining lycopene with the objective of improving the bioavailabilityof the latter and any novel raw material containing lycopene obtainedfrom a novel method of manufacture.

The quantity of carotenoid which can be used according to the inventionof course depends on the desired effect and may therefore vary to agreat extent.

To give an order of magnitude, in the composition according to theinvention, the carotenoid in the pure state is in a quantityrepresenting from 10⁻¹²% to 20% of the total weight of the compositionand preferably in a quantity representing from 10⁻⁸% to 10% of the totalweight of the composition.

Of course, persons skilled in the art, if they use the carotenoid in theform of a solution, a plant extract for example, know how to adjust thequantity of solution which they use in their composition so that thefinal quantity of carotenoid in the composition is consistent with theabove-defined quantities which can be used.

Lycopene is in particular known as an anti-free radical agent(JP-A-8-283136).

However, as indicated above, 7α-OH-DHEA, applied by the topical route,has itself an activity on the signs of skin aging, due in particular toits anti-free radical effects.

It will therefore be appreciated that the combination of a DHEAderivative according to the invention with a carotenoid makes itpossible to reinforce the anti-aging effects of the compositioncontaining them, in particular when this involves preventing or treatingthe signs of actinic skin aging.

The composition according to the invention is preferably suitable fortopical application to the skin. It may be provided in all the galenicforms normally used for this type of application, in particular in theform of an aqueous or oily solution, an oil-in-water or water-in-oil ormultiple emulsion, a silicone emulsion, a microemulsion or nanoemulsion,an aqueous or oily gel or a liquid, pasty or solid anhydrous product.

This composition may be fluid to a greater or lesser degree and may havethe appearance of a white or colored cream, an ointment, a milk, alotion, a serum, a paste, a mousse or a gel. It may be optionallyapplied to the skin in aerosol form. It may also be provided in solidform, for example in the form of a stick. It may be used as a careproduct and/or as a make-up product for the skin.

In a known manner, the composition of the invention may also contain thecustomary adjuvants in the cosmetic and dermatological fields, such ashydrophilic or lipophilic gelling agents, hydrophilic or lipophilicactive agents, preservatives, antioxidants, solvents, perfumes, fillers,screening agents, pigments, odor absorbers and coloring matter. Thequantities of these various adjuvants are those conventionally used inthe fields considered, and are for example from 0.01 to 20% of the totalweight of the composition. These adjuvants, depending on their nature,can be introduced into the fatty phase or into the aqueous phase. Theseadjuvants, and their concentrations, should be such that they do notadversely affect the advantageous properties of the DHEA derivatives, orof the carotenoids according to the invention.

When the composition according to the invention is an emulsion, theproportion of the fatty phase may range from 5 to 80% by weight, andpreferably from 5 to 50% by weight relative to the total weight of thecomposition. The fatty substances, the emulsifiers and the coemulsifiersused in the composition in the form of an emulsion are chosen from thoseconventionally used in the field considered. The emulsifier and thecoemulsifier are preferably present in the composition in a proportionranging from 0.3 to 30% by weight, and preferably from 0.5 to 20% byweight relative to the total weight of the composition.

As fatty substances which can be used in the invention, it is possibleto use oils and in particular mineral oils (liquid paraffin), oils ofplant origin (avocado oil, soybean oil), oils of animal origin(lanolin), synthetic oils (perhydrosqualene), silicone oils(cyclomethicone) and fluorinated oils (perfluoro-polyethers). It is alsopossible to use, as fatty substances, fatty alcohols such as cetylalcohol, fatty acids, waxes and gums, and in particular silicone gums.

As emulsifiers and coemulsifiers which can be used in the invention,there may be mentioned, for example, esters of fatty acids and ofpolyethylene glycol such as PEG-100 stearate, PEG-50 stearate and PEG-40stearate; esters of fatty acids and of polyols such as glycerylstearate, sorbitan tristearate, oxyethylenated sorbitan stearates whichare available under the trade names Tween® 20 or Tween® 60, for example;and mixtures thereof.

As hydrophilic gelling agents, there may be mentioned in particularcarboxyvinyl polymers (carbomer), acrylic copolymers such asacrylate/alkyl acrylate copolymers, polyacrylamides, polysaccharides,natural gums and clays, and, as lipophilic gelling agents, there may bementioned modified clays such as bentones, metal salts of fatty acidsand hydrophobic silica.

According to one variant of the invention, the composition may besuitable for administration by the oral route. In this case, it may beprovided in the form of syrups, suspensions, solutions, emulsions,granules, capsules or tablets, for example.

The daily doses of DHEA derivative which are administered by the oralroute may be between 1 and 100 mg/day, preferably between 25 and 75mg/day. Preferably, the DHEA derivative is present in the compositionaccording to the invention in a quantity allowing its administration ata dose between 50 and 100 mg/day, said dosage being obtained in one ormore doses, with a unit dose of 50 mg.

The daily doses of carotenoids administered by the oral route should bedefined on a case by case basis, according to the carotenoid involved.More particularly, in the case of beta-carotene or lycopene, the dailydoses administered may be between 1 and 500 mg/day, preferably at dosesbetween 1 and 50 mg/day.

In all cases, the composition according to the invention and/or thepreparation obtained therefrom comprises an effective quantity of DHEAderivative and an effective quantity of carotenoid, sufficient to obtainthe desired effect, in a physiologically acceptable medium.

The composition according to the invention finds application inparticular in the prevention and treatment of the signs of skin aging,in particular of actinic aging.

The present invention therefore also relates to the cosmetic use of theabovementioned composition for the prevention or treatment of the signsof skin aging, in particular of actinic aging.

It relates in particular to the cosmetic use of the compositiondescribed above for preventing or controlling the formation of wrinklesand/or for improving skin tone and/or for increasing skin firmness.

The present invention also relates to the cosmetic use of thecomposition described above for preventing or controlling the harmfuleffects of UV radiation on the skin.

It finally relates to the use of the composition described above formanufacturing a preparation intended for preventing or controlling theharmful effects of UV radiation on the skin.

The invention will now be illustrated by the following nonlimitingexamples. In these examples, the quantities are indicated as apercentage by weight.

EXAMPLE 1 Composition for Oral Administration

Soft gelatin capsules having the following composition are prepared in amanner which is conventional for persons skilled in the art:

Hydrogenated soybean oil 40 mg Wheat oil 95 mg Soybean lecithin 20 mgNatural tocopherols  5 mg Ascorbic acid 30 mg Beta-carotene 10 mg7α-OH-DHEA 50 mg

EXAMPLE 2 Composition for Oral Administration

Soft gelatin capsules having the following composition are prepared in amanner which is conventional for persons skilled in the art:

Hydrogenated soybean oil 40 mg Wheat oil 95 mg Soybean lecithin 20 mgNatural tocopherols  5 mg Ascorbic acid 30 mg Lycopene  6 mg 7α-OH-DHEA50 mg

EXAMPLE 3 Composition for Topical Application

A care cream (oil-in-water emulsion) having the following composition isprepared in a manner which is conventional for persons skilled in theart:

Lycopene at 6% 10⁻⁴% 7α-OH-DHEA   0.1% Glyceryl stearate    2%Polysorbate 60 (Tween 60 ® sold by the company    1% ICI) Stearic acid  1.4% Triethanolamine   0.7% Carbomer   0.4% Liquid fraction of sheabutter    12% Perhydrosqualene    12% Perfume   0.5% Preservative qsWater qs 100%

1. A composition comprising: a physiologically acceptable medium; atleast one DHEA derivative; selected from the group consisting of7-hydroxy-DHEA and 7-keto DHEA; and at least one carotenoid.
 2. Thecomposition as claimed in claim 1, comprising 7α-OH-DHEA.
 3. Thecomposition as claimed in claim 1, comprising 7β-OH-DHEA.
 4. Thecomposition as claimed in claim 1, wherein said carotenoid is at leastone of a natural carotenoids or a synthetic cartenoid.
 5. Thecomposition as claimed in claim 1, wherein said carotenoid is at leastone of a carotenoids with provitamin A activity or a carotenoids withoutprovitamin A activity.
 6. The composition as claimed in claim 5,comprising a carotenoid with provitamin A activity selected from thegroup consisting of β-carotene and α-carotene.
 7. The composition asclaimed in claim 6, comprising β—carotene.
 8. The composition as claimedin claim 6, comprising α—carotene.
 9. The composition as claimed inclaim 5, comprising a carotenoid without provitamin A activity selectedfrom the group consisting of zeaxanthin, lutein and lycopene.
 10. Thecomposition as claimed in claim 9, comprising lycopene.
 11. Thecomposition as claimed in claim 9, comprising lutein.
 12. Thecomposition as claimed in claim 9, comprising zeaxanthin.
 13. Thecomposition as claimed in claim 1, wherein the composition is fortopical application to the skin.
 14. The composition as claimed in claim13, wherein the DHEA derivative is present in an amount of from0.0000001 to 10% by weight, relative to the total weight of thecomposition.
 15. The composition as claimed in claim 14, wherein theDHEA derivative is present in an amount of from 0.00001 to 5% by weight,relative to the total weight of the composition.
 16. The composition asclaimed in claim 13, wherein the cartenoid is present in an amount offrom 10⁻⁸% to 10% by weight, relative to the total weight of thecomposition.
 17. The composition as claimed in claim 1, wherein thecomposition is for administration by the oral route.
 18. A processcomprising: administering the composition of claim 1 orally.
 19. Aprocess comprising: applying the composition as claimed in claim 1 tothe skin of a human in an amount effective for treating the aging ofskin.
 20. A process comprising: applying the composition as claimed inclaim 1 to the skin of a human in an amount effective for improving skintone or increasing skin firmness.
 21. A process comprising: applying thecomposition as claimed in claim 1 to the skin of a human in an amounteffective for reducing the harmful effects of UV radiation.
 22. Aprocess comprising: applying the composition as claimed in claim 1 tothe skin of a human in an amount that is effective for alleviating theharmful effects of UV radiation on the skin.